1. Field of the Invention
This invention relates to new camptothecin derivatives possessing anti-tumor activity (including carcinostatic activity) and to processes for the preparation of such derivatives. More particularly, this invention relates to new camptothecin derivatives carrying an aldehyde group or a functionally modified aldehyde group in the 7-position thereof and possessing anti-tumor activity with a low level of toxicity as well as processes for the preparation of such new camptothecin derivatives.
2. Description of the Prior Art
Camptothecin is a cytotoxic alkaloid isolated from leaves and barks of Camptotheca accuminata (Nyssaceae), a plant native to China, which has a pentacyclic structure consisting of a characteristic fused 5-ring system of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action and its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itself for clinical treatments is significantly limited because of high toxicity.
Accordingly, a number of attempts have been made to reduce the toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives. The chemical modifications so far reported are mainly about the rings D and/or E of camptothecin, but the results of such modifications revealed only failure in maintaining expected anti-tumor activity and poor improvement in toxicity [J. Med. Chem., 19 (1976), 675]. From the chemotherapeutic point of view, therefore, it is of importance that the chemical modifications of camptothecin should be restricted in the rings A, B and C without effecting any change in the rings D and E which are conceivable to be one of the essential structural elements for the expression of the above mentioned characteristic biological activities.
Except for a method for functionalizing the 12-position of camptothecin reported in 1976 which comprises a series of troublesome conversion and purification operations starting with nitration at the 12-position [P. Pei-chuang et al., Hau Hsueh Pao 33 (1975); Chem. Abstr. 84 (1976) 115629p], however, no success was reported until 1979 in connection with chemical functionalization of camptothecin in a moiety involving the rings A, B and C. This is probably ascribable to the reasons that camptothecin itself is only sparingly soluble in various organic solvents and that camptothecin possessing the nature of heterocyclic rings in its molecule is resistant to the so-called electrophilic reactions conventionally carried out on aromatic rings. In the present status, such obstacles strongly discourage chemical modifications of camptothecin contemplated academically for preparing new classes of derivatives thereof.
Under the above mentioned circumstances, the present inventors previously found together with co-workers a process for introducing a hydroxymethyl group into the 7-position of camptothecin efficiently in a single step and prepared a number of new camptothecin derivatives possessing anti-tumor activity with slight toxicity from 7-hydroxymethylcamptothecin obtained according to the above process (Japanese Laid-open Patent Applns. Nos. Sho. 56-12391, 56-12392, 56-12393 and 56-12394; U.S. Ser. No. 166,953; DOS No. 30 26 172). However, the kinds of camptothecin derivatives prepared according to these processes are still limited.
For further researches on the relation between the substituents in camptothecin derivatives and anti-tumor activity and/or toxicity, therefore, there is still a great demand in this art for developing further new classes of camptothecin derivatives possessing a low level of toxicity while maintaining the inherent anti-tumor activity by chemically modifying 7-hydroxymethylcamptothecin in a single step without destroying the structure of the rings D and E in the camptothecin molecule.